Project Summary In recent years, methamphetamine (METH) abuse has become a serious problem throughout the world and has been connected to several harmful medical complications, particularly psychiatric ones. Chronic METH abusers exhibit deficits in tasks requiring intact prefrontal cortex (PFC) function, and PFC dysfunction has been implicated in the loss of control over drug use. Previous studies have shown that the greatest neurocognitve impairments in METH addicts occur in attention, working memory, impulse control, cognitive flexibility and information processing. While considerable efforts have been made to understand the METH-mediated mechanisms underlying this altered behavioral response profile; an unfilled gap in knowledge exists regarding the synaptic and cellular mechanisms underlying METH-induced cognitive disabilities. We proposes that abstinence after METH self administration (SA) potentiates NMDA currents in parvalbumin positive (PV+), fast spiking interneurons (FSI) in a DAD1-dependent manner. The outcome of interneuron over-activation will be an imbalance in excitation/inhibition homeostasis resulting in hypofrontality and cognitive deficits. In order to tests our hypothesis we will use multidisciplinary techniques: whole cell recordings, behavioral tests and newly developed PV+:Cre rats combine with optogenetics. Whit these tools we will investigate the effects of METH self administration on PFC PV+FSI and pyramidal neurons excitability and working memory (Aim 1) and we will determine whether METH self administration-produced increases in PFC PV+FSI excitability is necessary and sufficient to produce working memory deficits (Aim 2). Since cognitive deficits occur in psychostimulant abusers and in a variety of different neurodevelopmental disorders, the knowledge generated by this proposal may provide new pharmacotherapeutics targets for multiple disorders that produce cognitive dysfunction.